Although psychostimulant drug abuse poses several potential health risks, the chronic abuse of amphetamines carries the danger of permanent brain injury. In animals, repeated administration of methamphetamine during the course of a single day produces long lasting damage to striatal dopamine and forebrain serotonin terminals. In addition, this drug produces a degeneration of pyramidal and stellate cells in the rat somatosensory cortex. Moreover, the degeneration of somatosensory cortical neurons appears to represent only the most visible form of methamphetamine's long term deleterious effects on cerebral cortex. Recent findings indicate that exposure to methamphetamine in animals reduces the immediate early gene responses of neurons in widespread cortical areas to dopaminergic agents, even long after the methamphetamine exposure. These findings agree with results from human methamphetamine abusers, indicating long lasting functional abnormalities in the cerebral cortex of abstinent addicts. The mechanisms underlying the long term suppression of cortical cell response are of particular interest because prior research concerning long term effects of methamphetamine has focused almost exclusively on mechanisms of injury to dopamine and serotonin terminals. The hypothesis underlying this application is that the long term reductions in cortical immediate early gene response of animals given methamphetamine relate to diminished basal ganglia gating of cortical function. Four specific aims are proposed to test this hypothesis: (i) to test the role of dopamine D1 and D2 receptors in the methamphetamine induced reductions in basal ganglia gating of cortical function;(ii) to establish the role of the striatum in the actions of dopamine in gating of cortical function;(iii) to determine whether methamphetamine affects the density or function of G proteins that couple dopamine with specific second messengers;and (iv) to investigate the effects of methamphetamine on signal transduction pathways leading to reduced cortical function. In aggregate, these experiments should provide a body of novel evidence concerning how methamphetamine addiction can alter cortical functions.